Cancer is a major burden to public health. Anticancer chemotherapy continues to be the most important adjuvant therapy to surgery, but multiple underlying cellular mechanisms complicate the treatment. Even when the treatment is initially effective, genomic instability causes the emergence of drug resistance, which is the most significant challenge in chemotherapy. Our previous research has shown that molecular nanofibers, formed by the self-assembly of innocuous monomers (e.g., D-peptides), selectively inhibit the growth of cancer cells in vitro and in vivo. This discovery promises novel anticancer agents that robustly target cancer cells while sparing normal cells. Particularly, enzyme-instructed molecular nanofibers inhibit several drug-resistant cancer cells (e.g., MES-SA/Dx5, SKOV3, and A2780cis) by mechanisms that differ fundamentally from those of conventional anticancer drugs that largely are based on ligand-receptor interactions. Thus, we propose to explore the enzyme-instructed molecular nanofibers of D-peptides as a paradigm-shifting approach that overcomes drug resistance in cancer. The central hypothesis of this research is that molecular nanofibers of D- peptides, spatiotemporally defined by enzymatic reactions, interact with multiple cellular proteins and interrupt multiple cellular processes to inhibit both drug sensitive and resistant cancer cells. The goal of this work is to elucidate how enzyme-instructed formation of molecular nanofibers of D-peptides inhibits cancer cells and ultimately to develop new nanomedicines to target drug-resistant cancer cells without harming normal cells. Specifically, this proposed research will (i) design and synthesize D-peptides for enzyme-instructed self- assembly to form molecular nanofibers (i.e., enzyme-instructed molecular nanofibers); (ii) evaluate the activity of the enzyme-instructed molecular nanofibers of D-peptides against drug-resistant cancer cells in cell culture;; (iii) identify the cellular location and protein targets of the molecular nanofibers of D-peptides and reveal the cellular processes perturbed by the molecular nanofibers of D-peptides; and (iv) evaluate the activity of the enzyme-instructed molecular nanofibers of D-peptides against drug-resistant cancer cells in ovarian cancer mouse models. This research explores the self-assembly of an underexplored molecular entity, D-peptides, thus providing a new platform for nanomedicine, based on enzyme reactions (rather than enzyme inhibition). We anticipate that this new approach will provide new molecules, novel technologies, and an unprecedented paradigm that will ultimately improve the survivorship of cancer patients.

Public Health Relevance

The overall goal of this work is to develop an innovative approach for creating molecular medicine to target cancer cells that are resistant to conventional chemotherapy without harming normal cells. Using enzymes to instruct the formation of nanoscale molecular assemblies (e.g., nanofibers) that kill cancer cells selectively, this approach will ultimately lead to a new paradigm of cancer therapy for the millions of people who will need anticancer treatment in the future, and thus improve health of the Nation.